Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine

Abstract

Background: D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, is synthesized from L-serine by serine racemase (SRR). Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life.

Methodology/principal findings: Neonatal mice (7-9 days) were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day), an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT), and prepulse inhibition (PPI) were performed at juvenile (5-6 weeks old) and adult (10-12 weeks old) stages. In addition, we tested the effects of D-serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70) significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure.

Conclusions/significance: This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult.

Figure 1. Spontaneous locomotion after neonatal Met-Phen treatment.

Saline (1.0 ml/kg/day) or Met-Phen (3.0 mg/kg/day) was administered i.p. from P7 to P9. Horizontal activity and rearing activity were performed at juvenile (5–6 weeks old) and adult stages (10–12 weeks old). Data represent the mean ± S.E.M. (n = 9 mice for control group, n = 16 for Met-Phen group). ***P<0.001 compared with saline treated group.

Figure 2. Cognition after neonatal Met-Phen treatment.

Saline (1.0 ml/kg/day) or Met-Phen (3.0 mg/kg/day) was administered i.p. from P7 to P9. NORT was performed at juvenile (5–6 weeks old) and adult stages (10–12 weeks old). Data represent the mean ± S.E.M. (n = 8–11 mice for control group, n = 11 or 12 for Met-Phen group). *P<0.05, **P<0.01, *** P<0.001 compared with saline treated group.

Figure 3. Auditory sensory gating PPI deficits after neonatal Met-Phen treatment.

Saline (1.0 ml/kg/day) or Met-Phen (3.0 mg/kg/day) was administered i.p. from P7 to P9. Auditory sensory gating PPI test was performed at juvenile (5–6 weeks old) and adult stages (10–12 weeks old). Data represent the mean ± S.E.M. (n = 11 mice for control group, n = 12 or 13 for Met-Phen group). *P<0.05 compared with saline treated group.

Figure 4. Effects of D-serine on PPI deficits at adult after neonatal Met-Phen treatment.

Met-Phen (3.0 mg/kg/day) was administered i.p. from P7 to P9. PPI test was performed at adult (10–12 weeks old). D-Serine (900 mg/kg, i.p.) or vehicle (saline; 10 ml/kg) was administered 30 minutes before PPI test. Data represent the mean ± S.E.M. (n = 7 mice for control group, n = 12 for D-serine group). *P<0.05, **P<0.01 compared with Met-Phen+vehicle treated group.

Figure 5. Preventive effects of D-serine on PPI deficits at adult after neonatal Met-Phen treatment.

Met-Phen (3.0 mg/kg/day) was administered i.p. from P7 to P9. PPI test was performed at adult (11 weeks old). D-Serine (900 mg/kg/day, i.p.) or vehicle (saline; 10 ml/kg/day, i.p.) was administered chronically from P35 (5 weeks old) to P70 (10 weeks old). PPI test was performed 1 week (P77) after the final administration of D-serine. Data represent the mean ± S.E.M. (n = 5 mice for control group, n = 5 for D-serine group). *P<0.05, **P<0.01, ***P<0.001 compared with Met-Phen+vehicle treated group.